Role of Proinflammatory Cytokines and Chemokines in Chronic Arthropathy in CHIKV Infection

Abstract

Chikungunya virus (CHIKV) has caused large outbreaks worldwide in recent years. Acute-phase CHIKV infection has been reported to cause mild to severe febrile illness, and in some patients, this may be followed by long-lasting polyarthritis. The mainstay of treatment includes nonsteroidal anti-inflammatory drugs and other disease-modifying agents, the use of which is based on the assumption of an immunological interference mechanism in the pathogenesis. The present study has been designed to generate preliminary evidence to test this hypothesis. The levels of 30 cytokines were estimated in serum samples of acute CHIKV-infected patients, fully-recovered patients, patients with chronic CHIKV arthritis, and controls, using a quantitative multiplex bead ELISA. The levels of the proinflammatory cytokines IL-1 and IL-6 were elevated in acute patients, but IFN-γ/β and TNF-α levels remained stable. IL-10, which might have an anti-inflammatory effect, was also elevated, indicating a predominantly anti-inflammatory response in the acute phase of infection. Elevation of MCP-1, IL-6, IL-8, MIP-1α, and MIP-1β was most prominent in the chronic phase. These cytokines and chemokines have been shown to play important roles in other arthritides, including epidemic polyarthritis (EPA) caused by Ross River virus (RRV) and rheumatoid arthritis (RA).The immunopathogenesis of chronic CHIKV arthritis might have similarities to these arthritides. The novel intervention strategies being developed for EPA and RA, such as IL-6 and IL-8 signaling blockade, may also be considered for chronic CHIKV arthritis.

A Novel Poxvirus-Based Vaccine, MVA-CHIKV, Is Highly Immunogenic and Protects Mice against Chikungunya Infection

“…Strong innate immune responses, with high levels of type I IFN, proinflammatory cytokines, and chemokines, have been detected in acute CHIKV-infected patients (64)(65)(66)(82)(83)(84)(85)(86)(87)(88)(89)(90), nonhuman primates (91), and mice (62-64, 66, 92, 93) and might play a critical role in controlling virus replication. Although high levels of some proinflammatory cytokines have been associated with disease severity (82)(83)(84)(85)(87)(88)(89), type I IFN was identified as a key mediator responsible for viral clearance, and IFN-stimulated genes (ISGs) or IFN response factors 3 and 7 have been described to be critical in the control of CHIKV infection (63,64,66,90,94,95). Moreover, IFN-␣/␤ knockout mice (A129 mice) exhibited severe CHIKV disease (62-64, 66, 92), confirming the key role of type I IFNs in the control of CHIKV infection, by restricting virus replication early in the infection, although their effects are not enough to eliminate CHIKV from infected hosts.…”

The Role of Innate versus Adaptive Immune Responses in a Mouse Model of O'Nyong-Nyong Virus Infection

“…[25][26][27][28][29] In humans, overlap has been identified between persistent CHIKV and rheumatoid arthritis; and proinflammatory mediators seem to play a role in disease progression and persistence. [30][31][32][33] However, the study of ONNV has received relatively little attention since its discovery, though it was the cause of one of the largest known arboviral outbreaks in the late 1950s and early 1960s in Uganda. Other than its clinical symptoms, very little is known about the pathogenesis of ONNV virus compared with CHIKV and RRV.…”

Chikungunya and Its Interaction With the Host Cell

“…According to these findings, Chaaithanya and colleagues (2011) and Kelvin and colleagues (2011) reported high levels of Th1-type cytokines in the blood of patients with chronic disease [86,87]. Thus, despite certain discrepancies, the available studies suggest that chronic disease is associated with a de-regulation of inflammation during the acute and convalescence phases.…”

“…Several studies have tried to identify the factors associated with chronic Chikungunya disease in groups of patients in Singapore [83], La Réunion [84], Dakshina Kannada (India) [85,86], and Emilia Romagna (Italy) [87]. Regulatory mechanisms silencing the vigorous (even localized) inflammatory response seem to be required to prevent the establishment of chronic disease weeks or even months after viral clearance from the blood.…”